Barrecheguren et al.

Respiratory Research (2018) 19:177

https://doi.org/10.1186/s12931-018-0882-0

REVIEW Open Access

What have we learned from observational

studies and clinical trials of mild to
moderate COPD?
Miriam Barrecheguren1, Cruz González2 and Marc Miravitlles1*

Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. It is well
established that patients with mild to moderate disease represent the majority of patients with COPD, and patients
with mild COPD already have measurable physiological impairment with increased morbidity and a higher risk of
mortality compared with healthy non-smoking individuals. However, this subpopulation is both underdiagnosed
and undertreated. In addition, most clinical trials include cohorts of patients with worse lung function and quality
of life, which are very different from the milder patients usually seen in primary care.
Clinical trials have shown that mild-moderate COPD patients present an improvement in lung function after treatment with
long-acting bronchodilators (LABD). Inhaled therapy has also shown benefits in terms of symptoms, health-related quality
of life (HRQL) and exacerbation prevention in this population. Early intervention might have also a positive effect to prevent
functional impairment. Nevertheless, there is scarce evidence from randomised clinical trials and real-life studies about the
importance of pharmacological treatment in early stages of COPD to improve long-term outcomes. New concepts such as
clinically important deterioration may help to investigate the impact of interventions on the natural history of the disease.
Keywords: COPD, Diagnosis, Epidemiology, Guidelines, Mild-moderate disease, Physical activity, Quality of life, Treatment

Background
Chronic obstructive pulmonary disease (COPD) is char-
acterised by chronic airflow limitation, which is usually
progressive. This disease is a major cause of morbidity
and is currently the fourth leading cause of death world-
wide [1, 2]. Although it is mostly related to exposure to
tobacco smoking, patients exposed to biomass and pol-
lution are also at risk of developing COPD.
The impact of COPD on each patient depends on the
degree of airflow limitation, the severity of symptoms
and comorbidities. The Global Initiative for Chronic Ob-
structive Lung Disease (GOLD) staging system categorises
COPD into 4 severity stages (based on post-bronchodilator
FEV1): stage I or mild, FEV1 ≥ 80% predicted; stage II or
moderate, FEV1 ≥ 50% and < 80% predicted; stage III or se-
vere, FEV1 ≥ 30% and < 50% predicted; and stage IV or very
* Correspondence: mmiravitlles@vhebron.net
1
Pneumology Department, Hospital General Universitari Vall d’Hebron, CIBER
de Enfermedades Respiratorias (CIBERES), P. de la Vall d’Hebron, 119-129,
08035 Barcelona, Spain
Full list of author information is available at the end of the article
severe, FEV1 < 30% predicted [3]. As the disease pro-
gresses, there is greater restriction in daily activity with
impaired quality of life and an increase of symptoms and
exacerbations.
Nonetheless, the reduction in daily activity is already
present in mild disease [4]. Since COPD is progressive, it
is important to identify and treat patients at early stages in
order to prevent further deterioration. Patients with mild
(stage I) COPD already have measurable physiological im-
pairment with increased morbidity and a higher risk of
mortality compared with healthy non-smoking controls
[5]. It is well established that patients with mild to moder-
ate disease represent the majority of patients with COPD
[6]. However, this subpopulation is both underdiagnosed
and undertreated [7]. In addition, most clinical trials in-
clude cohorts of patients with worse lung function and
worse quality of life, which are very different from those
usually seen in primary care (PC) [8].
Encouragement of smoking cessation, in conjunction
with management of symptoms and treating activity lim-
itations and exacerbations by appropriate pharmacologic

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Barrecheguren et al. Respiratory Research (2018) 19:177 Page 2 of 11

and non-pharmacologic management at the earliest pos-
sible stage can positively affect the impact and progres-
sion of the disease [9]. In recent years, newer strategies
and a growing number of new pharmacologic agents to
treat COPD have also been introduced and show prom-
ise in improving the management of COPD [10]. New
disease lung models to predict patient-specific drug de-
position are also being developed in order to individual-
ise therapy [11].
The aim of this article is to review the current evidence
on the epidemiology, natural history and management of
mild to moderate COPD (defined as an FEV1 > 50% pre-
dicted), highlighting the importance of treatment in earlier
stages of the disease to try to prevent progression.
Epidemiology and natural history
The World Health Organization estimates that up to
328 million people around the world have COPD with a
global prevalence of 1% [12]. This prevalence increases
to 8–10% for individuals above 40 years old [13]. A re-
cent systematic review aimed at estimating the preva-
lence of COPD across world regions among people aged
30 years or more found an overall prevalence of 10.7%
in 1990, which increased to 11.7% in 2010 (14.3% in
men and 7.6% in women) [14]. However, the prevalence
of COPD varied widely among world regions, being the
highest in the American region (14.1%), and the lowest
in South East Asia (7.8%) [14]. This variability might be
explained by differences in exposures and environmental
and genetic factors. Indeed, according to the BOLD
study, conducted at 12 sites around the world (n = 8775),
the overall prevalence of COPD ranged from 11.4 to
26.1%; the prevalence of GOLD I being between 1.4–
15.5% and the prevalence of GOLD II between 5.1 and
12.4% [6]. The Latin American Project for the Investiga-
tion of Obstructive Lung Disease (PLATINO) examined
the prevalence of COPD in adults > 40 years of age and
reported crude rates of GOLD stage I between 5.2 and
12.5% and GOLD II between 1.9 and 6.4% in five Latin
American countries [15]. Another systematic review esti-
mated a pooled prevalence for GOLD I of 9.8% (95%
confidence interval (CI) 5.9–15.8) and of 5.5% for GOLD
II (95%CI 3.3–9.0) [13].
In Europe, a systematic review by Atsou et al. [16]
found a prevalence of COPD from 2.1 to 26.1% depend-
ing on the country, the age group and the methods used,
the majority being GOLD I and II.
In Spain, the IBERPOC study conducted in 1997
showed a mean prevalence of COPD of 9.1% in subjects
between 40 and 69 years of age [17]. Ten years later, the
EPI-SCAN trial estimated a prevalence of 10.2% in sub-
jects between 40 and 80 years of age [18]. A sub-analysis
of these studies reported an increase of patients in
milder stages over time, ranging from 38.3% for mild
and 39.7% for moderate in the 1997 study to 85.6% for
mild and 13.0% for moderate in the 2007 study [19].
Despite the wide variability of the results found in these
population-based studies, the majority of the patients di-
agnosed had mild or moderate COPD, independently of
the classification criteria used (Table 1).
One of the main concerns in COPD is underdiagnosis,
which is more marked in early stages of the disease. It
has been estimated that 73–78% of patients with GOLD
stages I-II COPD remain undiagnosed [18]. Llordés et al.

Table 1 Prevalence of COPD GOLD I and II in some epidemiological studies of COPD

Study Country Prevalence (%)
GOLD I GOLD II
Halbert et al. [13] Worldwide All 7.6 (6.0–9.5)
9.8 (5.9–15.8) 5.5 (3.3–9.0)
Buist AS, et al. (BOLD) [6] Guangzhou 5.9% 7.6%
Salzburg 16.3% 9.3%
Cape town 6.5% 14.2%
Reykjavik 9.7% 6.7%
Krakow 14.4% 10.3%
Manila 0.9% 11.3%
Menezes AM, et al. (PLATINO) [15] Sao Paulo 10.1% 4.6%
Santiago 11% 4.9%
Mexico City 5.2% 1.9%
Montevideo 12.5% 6.4%
Caracas 6.4% 4.9%
Miravitlles M et al. (EPISCAN) [18] Spain All 10.2%
5.7% 3.9%
Barrecheguren et al. Respiratory Research (2018) 19:177
carried out a study to quantify the rate of underdiagnosis
and the accuracy of COPD diagnosis in PC [20]. The
study included 1738 subjects over the age of 45 with a
history of smoking and found a rate of underdiagnosis of
73%. Recently, the same group performed a case-finding
study in smokers or former smokers older than 40 years
and found a prevalence of COPD of 26.7%, with the ma-
jority of patients being in GOLD stages I and II (42.1
and 49.1%, respectively) [21]. Up to 29% of patients with
underdiagnosed COPD are asymptomatic [22], which
contributes to late detection. In addition, patients often
under-recognize the significance of respiratory symp-
toms, or they may accept that their symptoms are
caused by smoking and ignore them rather than consult.
Another cause for underdiagnosis might also be a defi-
cient active search for COPD by health care profes-
sionals [21]. Some of the diagnostic initiatives that have
been tested to improve COPD diagnosis are early detec-
tion programs [23] and other tools such as the use of
peak-flow meters or mini spirometers [24], and screen-
ing questionnaires [21, 25].
In contrast to underdiagnosis, the definition of COPD
based on FEV1/FVC instead of lower limit of normality
(LLN) might lead to the overdiagnosis of mild COPD in
individuals older than 65 years old [26].
The natural history of COPD is usually described by
the rate of decline in lung function. The rate of decline
in FEV1 in GOLD stages I-II is faster than in patients
with stages III-IV [27–29]. Recently, in a cohort of
smokers and ex-smokers, the COPD Gene group showed
that functional alteration of the small airways measured
by computerized tomography was significantly associ-
ated with a decline of FEV1, particularly in mild to mod-
erate stages of the disease, and this association was also
evident even before the detection of obstruction in the
spirometry [30].
Exacerbations have a negative impact on the natural his-
tory of COPD, and their presence has been associated
with a faster decline of FEV1, in particular in GOLD
stagesI and II [31], in which the effect of each exacerba-
tion on rate of FEV1 decline has been estimated to be −
23 ml/year in GOLD 1 and − 10 ml/year in GOLD 2 for
any exacerbation, increasing up to -87 ml/year and
-20 ml/year for GOLD 1 and 2 respectively for each severe
exacerbation. Frequent exacerbators also have a worse
quality of life and an increased risk of death [32–34].
Thus, the prevention of exacerbations should be a target
for every COPD patient, irrespective of the severity of the
disease.
Symptoms, quality of life and physical activity
COPD is defined by the presence of chronic respiratory
symptoms, among which exertional dyspnoea, cough
and sputum production are the most frequent [35].
Page 3 of 11
Although more severe patients present a higher intensity
of symptoms, there is not always a clear relationship be-
tween the degree of airflow obstruction and the presence
and impact of respiratory symptoms in a patient with
COPD [35, 36]. The observational study ASSESS charac-
terised the symptoms of COPD during 24 h and assessed
their relationship with patient-reported outcomes [37].
The analysis showed that the frequency of symptom oc-
currence was high for any degree of bronchial obstruc-
tion, with a prevalence of symptoms in GOLD stages I-II
of 84–88%.
The presence of respiratory symptoms in patients with
early COPD may modify long-term FEV1 decline and
health-related quality of life. Symptomatic subjects with
GOLD I COPD have a more rapid long-term decline in
lung function than asymptomatic subjects [38, 39].
Despite referring fewer symptoms, mild COPD pa-
tients present exercise limitation that leads to changes in
lifestyle and deconditioning, with an increasing burden
of the disease beyond the degree of airflow obstruction.
Indeed, around two thirds of GOLD stage II patients
may have significant lung hyperinflation [40]. This
hyperinflation is manifested as exertional dyspnoea, and
furthermore, dyspnoea significantly contributes to a
worse quality of life due to the high impact on their daily
activities [41]. Even mild patients may have severe dys-
pnoea; a study carried out in 5299 subjects found that
7.5 and 18.3% of subjects with GOLD stages I and II, re-
spectively, had a Medical Research Council (MRC)
score ≥ 3 [42]. Similarly, a large European observational
study conducted in 1817 patients in PC showed a high
prevalence of symptoms in GOLD II patients (cough
76.6%, sputum 64.1%, and dyspnoea 67.3%). Moreover,
31% had a MRC dyspnoea grade ≥ 3. [43]. In a recent
analysis carried out in 49,438 COPD patients, 50.2%
were GOLD stage II, and 37.1% had a MRC dyspnoea
grade ≥ 3, demonstrating that significant dyspnoea can
be present in early stages of the disease [44]. In addition
to being the most frequent symptom, dyspnoea has
proven to be a better predictor of death at 5 years than
airway obstruction in patients with COPD [45].
Concerning quality of life, the study by Jones et al.
[43] using the St. George’s Respiratory Questionnaire
[SGRQ] and the 12-Item Short Form Survey [SF-12]
demonstrated that GOLD I and II patients had an im-
paired quality of life compared with healthy individuals.
These results are similar to those obtained in the
EPI-SCAN study, which observed a significant impair-
ment of health-related quality of life in all severities of
COPD, even GOLD I and II and undiagnosed COPD pa-
tients [18].
Physical activity significantly deteriorates in patients
with COPD as the disease progresses [46], and the re-
duction in physical activity is one of the best predictors
Barrecheguren et al. Respiratory Research (2018) 19:177
for COPD survival [47]. In addition, physical inactivity is
strongly associated with the presence of comorbidities
[48]. In contrast, regular physical activity reduces hospi-
talisation and the risk of death in COPD [49]. However,
even in early stages of the disease, most patients with
COPD spend less time walking (and walking more
slowly) and standing, and more time sitting and lying
compared with sedentary healthy elderly subjects [50].
Treatment of mild to moderate COPD
The main objectives for the treatment of COPD are the
reduction of symptoms, the reduction of frequency and
severity of the exacerbations and the improvement of
prognosis [3, 51]. Non-pharmacological treatment, espe-
cially smoking cessation, is essential for every COPD pa-
tient and ha sproven to be the most efficient and
cost-effective therapeutic strategy [3, 51]. Smoking cessa-
tion slows the loss of lung function and improves survival.
Indeed, the benefits may be more evident in milder pa-
tients than in individuals with a more established disease
[52]. Psychotherapy might be beneficial in addition to ex-
ercise and medication. Other non-pharmacological ap-
proaches include regular physical activity, an adequate
nutrition status, management of comorbidities, and vac-
cination against pneumococcal and influenza viruses is
also recommended for all patients. Pulmonary rehabilita-
tion has shown to improve symptoms, exercise tolerance
and health-related quality of life, and to reduce the risk of
morbidity from acute exacerbations of COPD [53]. Both a
meta-analysis and a systematic review concluded that pa-
tients with mild to moderate COPD also benefit from
short- and long-term rehabilitation [54, 55]. Hence, con-
sidering the benefits of physical activity, patients with
COPD should be encouraged to increase their level of ex-
ercise from early stages.
Real-life experience of treatment of mild-moderate COPD
Mild COPD patients are frequently followed in a PC set-
ting, and they are usually not included in randomised con-
trolled trials (RCT) [8], therefore, database studies could
provide interesting data on the management of these sub-
jects. An analysis of real-life prescribing patterns in primary
care in the UK described the treatment of 24,957 COPD
patients among which half were GOLD II [56]. Up to 17.7%
did not receive any treatment for their disease, and 14%
were treated only with short-acting β-agonists (SABA) des-
pite being symptomatic. In fact, two thirds of the untreated
patients referred a COPD Assessment Test (CAT) score >
10, while 22.7% had a modified MRC ≥ 2, consistent with
highly symptomatic disease. Moreover, a high percentage of
treated patients remained symptomatic: 36.6% of patients
had a modified MRC ≥ 2, and 76.4% had a CAT score ≥ 10
with their current treatment regimen.
Page 4 of 11
In a similar study that included 7881 newly diagnosed
COPD patients in PC, 54.3% had GOLD stage II at the
time of diagnosis. Initially, 37.9% were treated only with
short-acting bronchodilators (SABD) or did not receive
any inhaled treatment, while only one third of the pa-
tients were prescribed a long-acting bronchodilator
(LABD), alone or in combination with inhaled cortico-
steroids (ICS) [57]. Raluy-Callado et al. [58] described
the treatment patterns in a population of prevalent and
incident COPD patients, of whom 53.5 and 61% were
GOLD stage II, respectively. The authors found that al-
most half of the incident patients with FEV1 > 50% and
infrequent exacerbations were prescribed monotherapy,
being SABD the most frequent (29.3%) [58]. Similar re-
sults have been observed in other countries. In Catalonia
(Spain), a recent study showed that 55.2% of the patients
diagnosed in PC had GOLD stage II COPD. After the
diagnosis of the disease, GOLD II patients frequently
remained untreated (28.1%) or were treated only with a
SABD (18.5%) [59].
The reasons for undertreatment are varied. COPD pa-
tients often do not seek medical help until the symptoms
interfere with their daily life, and asymptomatic patients
are also less likely to be identified and to receive treat-
ment. In addition, some patients tend to reduce their
physical activity even at early stages of the disease, which
might help to minimize symptom perception. Moreover,
mild COPD patients are more likely to experience unre-
ported exacerbations [60], which may contribute to an
underestimation of the impact of COPD. Another pos-
sible reason for undertreatment is a lack of awareness of
guideline recommendations.
Clinical trials of pharmacological treatment of mild to
moderate COPD
Clinical trials usually include patients with moderate or
severe COPD; hence, the data available on the benefits
of inhaled treatment in mild COPD patients are limited.
This is in contrast with the distribution of severity in a
real-life setting, with up to 50% of the COPD patients
controlled in PC being GOLD stage II [16, 59]. However,
there is some evidence of the efficacy of treatments in
GOLD stage II COPD patients derived from studies on
mild-moderate COPD and subgroup analysis of RCTs
(Table 2).
Lung function
The effects of the treatments are measured by different
outcomes: lung function, dyspnoea, quality of life and
exacerbations. In terms of lung function, in a 12-week
placebo-controlled study conducted in Germany, treat-
ment with tiotropium showed a significant increase of
trough FEV1 (+ 79 ml), which was even more pro-
nounced in COPD patients with a FEV1 between 50 and
Barrecheguren et al. Respiratory Research (2018) 19:177 Page 5 of 11

Table 2 Results in GOLD stage II COPD patients in randomised clinical trials

Study Treatment GOLD stage Results
II patients (n)
Decramer M, et al. Tiotropium vs. placebo 2739 - Lower rate of decline of mean
UPLIFT study [66] postbronchodilator FEV1
- improvement in the SGRQ
- increase in the time to first
exacerbation
Beeh KM, et al. [61] Tiotropium vs. placebo 586 - increment in trough FEV1
Duser D, et al. Tiotropium vs. placebo 426 - reduction in the number of
Mistral study [68] exacerbations
Freeman D, et al. Tiotropium 185 - improvement in trough FEV1
SPRUCE study [62] - reduction in the number of
exacerbations
Singh D, et al. Tiotropium/olodaterol vs. tiotropium or placebo 1042 - improvement in the trough FEV1
OTEMTO study [64] - improvement in symptoms
and the SGRQ
Vincken W, et al. [88] Tiotropium vs. ipratropium 535 - improvement in trough FEV1
- improvement in PEFR, salbutamol
use, TDI, and SGRQ
- reduction in the number of
exacerbations
Casburi R, et al. [89] Tiotropium vs. placebo 921 - improvement in trough FEV1
- reduction in dyspnoea
- improvement in health status scores
- reduction in the number of
exacerbations
Jenkins C, et al. SFC vs. placebo 2156 - reduction in the risk of death
TORCH study [63] - improvements in FEV1
- reduction in the annual rate
of exacerbations
Jones PW, et al. Fluticasone propionate vs. placebo 391 (mild) - reduction in the number of
ISOLDE study [90] 359 (moderate-severe) exacerbations (less in mild disease)
Vestbo J, et al. Fluticasone fuorate vs. placebo 4135 vs 4121 vs 4118 - reduction in the rate of decline in FEV1
SUMMIT study [77] vs. vilanterol vs. combination therapy - reduction in the rate of
moderate and severe exacerbation
Vogelmeier CF, et al. Indacaterol/glycopyrronium vs. 811 vs. 269 - greater improvement on trough FEV1
CRYSTAL study [65] LABA/ICS vs. LABA or LAMA 811 vs. 268 - greater improvement in dyspnoea
- greater improvement in health status
- lower rescue medication use
Wedzicha JA, Indacaterol/glycopyrronium vs. SFC 1680 vs. 1682 - superiority in reducing annual rate of exacerbations
et al. [69] - longer time to the first exacerbation
FEV1 forced expiratory volume in one second, ICS inhaled corticosteroids, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, PEFR peak
expiratory flow rate, SFC inhaled salmeterol plus fluticasone propionate, SGRQ St George’s Respiratory Questionnaire, TDI transition dyspnoea index

70% (trough FEV1 + 113 ml) [61]. In a PC setting,
GOLD I and II patients also showed a trend to improv-
ing trough FEV1 with tiotropium compared with placebo
after 12 weeks [effect size 40 ml (95%CI -30, 100)] [62].
The efficacy of the inhaled salmeterol/fluticasone com-
bination (SFC) in patients with mild COPD is limited. A
post hoc analysis of the TORCH study, which included
2156 subjects with FEV1 > 50% showed an increase in
FEV1 in GOLD II patients treated with 101 ml of SFC
compared with placebo [63].
The combination of a long-acting antimuscarinic agent
(LAMA) and a long-acting beta-2 agonist (LABA) (tio-
tropium/olodaterol) has also shown to improve trough
FEV1 compared to placebo (149 ml versus − 10 ml,
respectively) in GOLD stage II patients [64]. In the
CRYSTAL study, which included 2160 patients with
moderate COPD, the effect of the LABA/LAMA indaca-
terol/glycopyrronium was superior to LABA/ICS in
trough FEV1 at week 12 (treatment difference + 71 ml)
and to LABA or LAMA monotherapies (difference +
101 ml) [65].
Dyspnoea
Inhaled therapy has also shown benefits in GOLD II pa-
tients in terms of symptoms. Treatment with tiotro-
pium/olodaterol improved dyspnoea measured by the
Transition Dyspnea Index (TDI) compared to placebo
(1.67versus 0.39) [64]. The CRYSTAL study also showed
Barrecheguren et al. Respiratory Research (2018) 19:177
superior improvement in the total TDI score with inda-
caterol/glycopyrronium versus LABA/ICS (difference
1.10 units) and versus LABA or LAMA (difference
1.26 units) in GOLD stage II COPD patients [65].
Quality of life
Regarding quality of life, in the UPLIFT study, the authors
observed an improvement in health status measured by
the SGRQ at all time points in the tiotropium group (p ≤
0.006 for all time points) [66]. In the TORCH study,
GOLD II COPD patients also experienced a better health
status when treated with SFC in comparison with placebo
(change in the SGRQ − 2.3), although the minimal clinic-
ally important difference was not reached [67]. The
combination of tiotropium/olodaterol showed a greater
improvement, with a change from baseline in the SGRQ
score of − 4.7 compared with − 2.2 in the tiotropium arm,
and − 0.7 in the placebo arm in GOLD II patients [64].
Exacerbations
The effects of treatment on exacerbation prevention in
moderate COPD have been demonstrated in several
studies. Tiotropium has shown to prevent exacerbations
in patients with less severe COPD. In the MISTRAL
study, the number of exacerbations in the subgroup of
patients with a FEV1 ≥ 50% was lower for those receiving
tiotropium compared to placebo (1.21 versus 1.97, re-
spectively; p < 0.01) [68]. The UPLIFT study also showed
that the time to the first exacerbation and the time to
exacerbation resulting in hospital admission were longer
in the tiotropium group than in the control group in the
GOLD II subgroup (hazard ratio 0.82, 95% CI 0.75–0.90,
and 0.74, 0.62–0.88, respectively) [66]. In PC, patients
with FEV1 > 50% that received tiotropium in addition to
their usual treatment were less likely to have ≥1 exacer-
bation during follow-up compared to the placebo group
(6.8% versus 16.8%) [62].
Treatment with SFC has also demonstrated to reduce the
annual rate of exacerbations by 31% in GOLD stage II
COPD patients compared with placebo (mean of 0.57/year
versus 0.82/year, respectively) [68]. The combination
LABA/LAMA is also effective in reducing exacerbations. In
fact, the superiority of indacaterol/glycopyrronium over
monotherapies and LABA/ICS was demonstrated in several
phase III clinical trials, including the FLAME study, which
showed that this combination was superior to SFC in redu-
cing the annual rate of exacerbations, although in patients
with moderate COPD the difference did not reach signifi-
cance, probably due to an insufficient sample size of pa-
tients with this level of severity (HR 0.93 (0.82–1.06)) [69].
These studies suggest that in general, treatment of
mild to moderate COPD should be started with one or a
combination of two LABD. The only exception would be
asthma-COPD overlap (ACO) patients, who usually have
Page 6 of 11
more respiratory symptoms, but especially a better re-
sponse to ICS [70].
Impact of early treatment on the natural history
of COPD
Since the decline in lung function is faster in early stages of
the disease, early intervention is required to prevent func-
tional impairment [71]. However, there are only a few
large-scale clinical trials on long-term interventions in pa-
tients in early stages of COPD. The Lung Health Study, car-
ried out in 3926 smokers with mild to moderate airway
obstruction for a period of 5 years showed that participants
who stopped smoking experienced an improvement in
FEV1 in the year after quitting (average of 47 ml or 2%),
and that the subsequent rate of decline in FEV1 among sus-
tained quitters was half the rate of that of continuing
smokers (31 ml versus 62 ml, respectively), and comparable
to that of never-smokers [72]. A post hoc analysis of the UP-
LIFT study that included only GOLD II patients observed
that the rate of decline for postbronchodilator FEV1 was
lower in the tiotropium group than in the control group
(43 ml per year [SE 2] vs. 49 ml per year [SE 2], p = 0.024)
[66]. Another sub-analysis from UPLIFT assessed the efficacy
of treatment with tiotropium in patients without previous
maintenance treatment (naïve patients) and included a ma-
jority of GOLD II (60%). The annual FEV1 decline was
slower in the tiotropium group (35 ml (SD 3) in the tioptro-
pium arm vs. 45 ml (SD 4) in the placebo arm) [73].
More recently, in a randomised placebo-controlled trial
which included 841 mild to moderate COPD patients,
Zhou et al. [74] observed that the annual FEV1 decline in
early stage COPD was lower in patients treated with tio-
tropium (29 ml ±5) than in the placebo group (51 ml ± 6;
difference 22 ml (95% CI 6 to 37). In the TORCH study,
SFC also showed a reduction in the rate of decline in
FEV1 versus placebo in the GOLD II group (difference
16 ml/year, 95% CI: 0, 32) [63]. These results were con-
firmed in the SUMMIT study, in which GOLD II patients
also had a lower rate of decline in FEV1 in the fluticasone
furoate/vilanterol arm compared to placebo (38 ml (2.4)
vs. -46 ml (2.5) respectively, p = 0.019) [75]. These results
should be considered in the context of both studies failing
to reach their primary outcome of mortality (Table 3).
With regard to mortality, the TORCH study showed a
33% reduction in the risk of death in GOLD stage II
COPD patients (HR 0.67; 95% CI: 0.45, 0.98) with SFC
compared with placebo [63]. In UPLIFT, there was a
non significant reduction in mortality with tiotropium
compared to placebo (hazard ratio [HR], 0.89; 95% CI,
0.79 to 1.02, p = 0.09) [76]. More recently, treatment
with fluticasone furoate/vilanterol showed no effect on
mortality in COPD patients with FEV1 > 50% and car-
diovascular risk (HR 0·88 [95% CI 0·74–1·04]; 12% rela-
tive reduction; p = 0.137) [77].
Barrecheguren et al. Respiratory Research (2018) 19:177
Table 3 Impact of early pharmacological treatment on rate of FEV1 decline
Study Participants
Scanlon PD et al. [72] 3926 smokers
Decreamer M, et al. [66] 2375 GOLD II
Troosters T et al. [73] 120 GOLD II
Zhou Y et al. [74] 841 GOLD I and II
Jenkins CR et al. [63] 2156 GOLD II
Calverley PMA, et al. [75] 6981 GOLD II
FEV1 forced expiratory volume in one second, SFC salmeterol/fluticasone fixed dose combination
Deterioration prevention
Improvement of clinical and/or spirometric parameters
are the endpoints routinely assessed to evaluate the effects
of treatments in COPD in most RCTs. However, many pa-
tients do not improve and suffer progressive deterioration
of their disease. Taking into account that deterioration of
lung function, exacerbation frequency, and health status
are important parameters to reflect the impact of treat-
ment on COPD management [32, 78–81], the evaluation
of composite endpoints may be more sensitive than indi-
vidual measures to the effects of therapeutic interventions.
One of the proposed composite endpoints is the so-called
clinically important deterioration (CID). This endpoint al-
lows assessing the rate of deterioration of lung function,
exacerbation rate and/or health status of the patient and
evaluates the effects of treatment. In addition, this com-
posite endpoint is consistent with the current GOLD
strategy, which recommends that lung function, COPD
exacerbation risk, and health status are considered when
assessing disease progression and severity [3].
A post hoc pooled analysis of three RCTs assessed
short-term CID in maintenance-naïve patients with
COPD receiving the combination of umeclidinium and
vilanterol(LAMA/LABA) compared with tiotropium for
6 months [82].The results showed that early use of
dual-bronchodilator therapy has superior efficacy in lung
function and may reduce the risk of short-term CID
compared to monotherapy in symptomatic patients with
COPD [82].
Another analysis described the effect of the combin-
ation of another LAMA/LABA, indacaterol/glycopirro-
nium versus both tiotropium or SFC on the prevention
of CID using patient data from three large phase 3 RCTs
[83]. The study used two different definitions for CID:
definition 1 was a composite of ≥100 ml decrease in
FEV1, a ≥ 4-unit increase in SGRQ, and a moderate to
severe COPD exacerbation, while for definition 2, the
FEV1 component was replaced by a ≥ 1-unit decrease in
the TDI. This analysis confirmed the utility of the CID
Page 7 of 11
Follow-up Intervention Outcome
5 years Quitting smoking Improvement in FEV1 (47 ml or 2%)
4 years Tiotropium vs. placebo Reduction in rate of FEV1 decline
(43 ml/year vs. 49 ml/year, p = 0.024)
4 years Tiotropium vs. placebo Reduction in rate of FEV1 decline
(35 ml vs. 45 ml)
2 years Tiotropium vs. placebo Reduction in rate of FEV1 decline
(29 ml vs. 51 ml)
3 years SFC vs. placebo Reduction in rate of FEV1 decline
(difference 16 ml/year, 95% CI 0,32)
15 to 44 months SFC vs. placebo Reduction in rate of FEV1 decline
(38 ml vs −46 ml, p = 0.019))
endpoint as a measurement of COPD worsening in pa-
tients with moderate to severe COPD and using this
endpoint the analysis showed that the combination of
indacaterol/glycopyrronium offers significant benefits
over treatment with a LAMA or a LABA/ICS both in
terms of the incidence and time to CID.
Another post hoc analysis evaluated CID using data
from two randomised phase III studies that assessed the
efficacy and safety of the combination of aclidinium/for-
moterol in patients with COPD [84]. The results demon-
strated that this combination reduced the risk of a first
CID, providing greater airway stability, and therefore,
fewer deteriorations in lung function, dyspnoea, risk of
exacerbations, and health status compared with placebo
or monotherapies.
Current treatment guidelines
A recent review of COPD treatment guidelines pub-
lished in Europe and Russia in the last 7 years found that
although there were differences in some recommended
treatments, there was a general agreement on treatment
goals and the use of LABD as the cornerstone of COPD
treatment [85].
The GOLD strategy establishes pharmacologic treat-
ment algorithms by groups of different risk and intensity
of symptoms. For patients in GOLD group A (low risk
and low symptom burden), a bronchodilator should be
offered to reduce breathlessness. For patients in GOLD
group B (low risk and high symptom burden), the pre-
ferred initial therapy should be a LABD. If the symptoms
persist, therapy with two bronchodilators may be consid-
ered [3].
The National Institute for Health and Care Excellence
(NICE) guidelines updated in 2010 recommended that pa-
tients with FEV1 > 50% predicted with exacerbations or
persistent airflow obstruction should be offered LABDs,
and in the case of persistence of symptoms, patients
should receive either LABA/ICS or LAMA/LABA [86].
Barrecheguren et al. Respiratory Research (2018) 19:177
The Spanish COPD guidelines (GesEPOC) were devel-
oped based on risk stratification and clinical phenotypes
[51]. They use an easy risk classification (low or high
risk) based on lung function, dyspnoea grade, and his-
tory of exacerbations. The four clinical phenotypes iden-
tified were: non-exacerbator, ACO, exacerbator with
emphysema, and exacerbator with chronic bronchitis.
However, they only recommend the determination of
clinical phenotype in high-risk patients. Pharmacological
recommendations for low-risk patients consist of LABD
without any type of anti-inflammatory treatment, and
the initial treatment for most high risk patients consists
of LAMA/LABA [51].
The newest position statement of the Canadian Thor-
acic Society in COPD gives more weight to symptoms
and exacerbations when it comes to increasing or de-
creasing therapy. In symptomatic patients with stable
COPD without frequent exacerbations, treatment should
be started with a LABD, and if experiencing persistent
or increased dyspnoea, exercise intolerance, and/or re-
duced health status despite the use of monotherapy, pa-
tients should be considered for “step up” treatment with
a LAMA/LABA. In patients with stable COPD experien-
cing exacerbations despite the use of LAMA or LABA
monotherapy, “step up” treatment with inhaled LAMA/
LABA should be considered. If a patient is still experien-
cing exacerbations despite the use of LAMA/LABA,
“step up” treatment with LAMA plus LABA/ICS can be
considered. Since inhaled triple or dual therapy may not
prove to be superior in every patient, the notion of “step
down” treatment may be a consideration in some
Fig. 1 Proposal of treatment algorithm for the management of GOLD 1–2 COPD patients. COPD: chronic obstructive pulmonary disease; ACO:
asthma-COPD overlap; LAMA: long acting anti muscarinic; LABA: long acting b-2 agonists; ICS: inhaled corticosteroids
Page 8 of 11
patients. For patients with suspected ACO, a combin-
ation of LABA/ICS is recommended [87]. Figure 1 pre-
sents a treatment algorithm for mild-moderate COPD
patients.
Conclusions
Although patients with mild to moderate disease repre-
sent the majority of patients with COPD, most studies
and in particular RCTs are focused on severe COPD pa-
tients. Moreover, mild to moderate patients tend to be
underdiagnosed and undertreated, affecting their prog-
nosis and quality of life. Since COPD is progressive, it is
important to identify and treat patients at early stages in
order to prevent further deterioration, even more con-
sidering that patients with mild COPD already have
measurable physiological impairment that leads to
changes in lifestyle and deconditioning.
Smoking cessation, management of symptoms and treat-
ing activity limitations and exacerbations by appropriate
pharmacologic and non-pharmacologic management at the
earliest possible stage could positively affect the impact and
progression of the disease, symptoms, exacerbations, and
quality of life. These benefits may be more evident in milder
patients than in COPD individuals with a more established
disease. Non-pharmacological management includes regular
physical activity, pulmonary rehabilitation, an adequate nu-
trition status, and management of comorbidities, and vac-
cination against pneumococcal and influenza viruses is also
recommended for all patients. On the other hand, early
treatment with one LABD or the combination of two bron-
chodilators has shown to produce a slightly greater
Barrecheguren et al. Respiratory Research (2018) 19:177
improvement in lung function in patients with GOLD stage
II than in those with more advanced stages of COPD, and
this improvement was associated with an improvement of
symptoms, health-related quality of life and a reduction in
the risk of exacerbations.
New studies suggest that early treatment with dual
bronchodilators may prevent disease deterioration, but
this interesting concept should be tested in large clinical
trials specifically designed for this objective.
Abbreviations
CAT: COPD Assessment Test; CID: Clinically important deterioration;
COPD: Chronic obstructive pulmonary disease; FEV1: Forced expiratory
volume in the first second; GOLD: Global Initiative for Chronic Obstructive
Lung Disease; ICS: Inhaled corticosteroids; LABA: Long-acting β-2 agonist;
LABD: Long-acting bronchodilator; LAMA: Long-acting antimuscarinic agent;
MRC: Medical Research Council; PC: Primary care; RCT: Randomised clinical
trial; SABA: Short-acting β-agonists; SABD: Short-acting bronchodilators; SF-
12: 12-item short form survey; SFC: Salmeterol/fluticasone combination;
SGRQ: St. George’s Respiratory Questionnaire; TDI: Transition dyspnoea index
Acknowledgements
Miriam Barrecheguren is the recipient of a Rio Hortega contract in the 2017
Strategic Action Health Call from the Instituto de Salud Carlos III for the years
2018-2019.
Funding
This work has been funded by an unrestricted grant from Laboratorios
Esteve S.A. (Barcelona, Spain). The funding body did not participate in any
stage of the preparation of the manuscript.
Authors’ contributions
MM, MB and CG have contributed equally to the development of the
manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
Marc Miravitlles has received speaker fees from Boehringer Ingelheim, Chiesi,
Cipla, Menarini, Rovi, Grifols and Novartis, and consulting fees from
Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Gebro Pharma, CSL Behring,
Novartis and Grifols.
Cruz González has received speaker fees from Novartis, Astra, Boehringer
Ingelheim, Chiesi, Menarini, and Rovi, and consulting fees from Astra,
Boehringer Ingelheim, Novartis and Esteve.
Miriam Barrecheguren has received speaker fees from Grifols and Menarini,
and consulting fees from GlaxoSmithKline.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Pneumology Department, Hospital General Universitari Vall d’Hebron, CIBER
de Enfermedades Respiratorias (CIBERES), P. de la Vall d’Hebron, 119-129,
08035 Barcelona, Spain. 2Pneumology Department, Hospital Clínic
Universitari, Valencia, Spain.
Received: 23 June 2018 Accepted: 5 September 2018
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